49 year-old female was in good health until July 2003 when she developed a severe flu-like illness.
The patient was living in Incline village, Lake Tahoe for 14 months. The patient had low-grade fever, chills, myalgia,
severe throat swelling followed by neck pain, without sinus congestion, cough, chest pain, headache or diarrhea. Physical
examination after one week of illness demonstrated neck tenderness. A complete blood count, comprehensive chemistry panel,
thyroid function test and erythrocyte sedimentation rate were normal The patient was told to have either a viral infection
or lupus. CT scan of the brain and spinal tap performed for the severe headache did not reveal any findings. Chest x-ray
was negative. Treatment with Medrol dose pack and Celebrex did not alleviate her symptoms, except the neck pain improved to
some extent. The symptoms of acute illness lasted about several weeks but the fatigue and neck pain never resolved. The
patient subsequent had relapsing symptoms of fatigue, myalgia, low-grade fevers, night sweats, sore throat and cervical
lymphadenopathy, cognitive dysfunction and debilitating headache. The patient received Medrol dose pack 4 different times
since the beginning of the illness. The illness spontaneously cycled every week with one good day at an energy level of 6/10
and 1-3 bad days a week with energy level of 2-4/10. She could not concentrate and had severe post-exertional fatigue for
2-3 days. She had been depressed and crying a lot. The patient was only able to work 20 hours a week, but had severe
fatigue after work requiring extra hours of sleep at night and on weekends to build up enough energy for work. She woke up
quite often especially when she was more tired. The maximal exercise she can perform now is walking one block whereas she
could swim and ski before he became ill. She would need to take a nap frequently. She has gained 20 lbs in one year.
Afterwards, she had to quit her job due to increasing fatigue.

IgG antibody to Epstein-Barr virus and CMV were minimally elevated, but the IgM antibody was negative. C. pneumoniae IgG
was 1:8. Antibody titers for coxsackievirus B1-6 and echoviruses 6,7,9,11,30 were not significantly elevated.

She tolerated the combination of alpha and gamma interferon poorly. Subsequently, she was treated with IVIG
every 3 months with mild improvement.

Assessment & Treatment: Chronic fatigue syndrome ≠ the patientís symptoms started in the summer
of 2003 following a flu-like illness. The nature of the illness was highly suggestive of enteroviral infection.
Incline village, the place where the infection was acquired had a major epidemic of CFS/ME in 1984, and the etiology
was never elucidated by the CDC investigators. However, lake water is known to have enteroviruses. The patient has
fulfilled the 2 major and 4 minor criteria for the diagnosis of CFS, as established by the CDC in 1994. The results
of the serological study were not diagnostic for acute EBV, CMV or enterovirus infections. The major drawback of the
serological testing is that neutralizing antibody tests are only available for 11 of 70+ non-polio enteroviruses.
However, enterovirus RNA was detected in the blood and the staining of the stomach biopsies demonstrated extensive
viral protein few years after the initial infection, consistent with chronic enterovirus infection . The use of medrol
dose pack during the acute phase of infection most likely shifted the immune response to the Th2 (T helper 2) direction,
which allow the viruses to persist in the body. She has mild to modest improvement with IVIG infusion given every 3
months.

CASE 2.

36-year-old white male who had been in remarkable health
until December 2004 when he had self-limited nausea and vomiting, followed
by mild fatigue and myalgia. He used to run 6 miles every other day
but had to cut back over the next several months. In April 2005, the
patient had sudden onset of vertigo, nausea and vomiting, then had dizziness,
headache and nausea two weeks later. In July 2005, the patient had severe
diarrhea, nausea, dizziness, blurred vision, cross-eyed feeling, dysequilibrium,
flu-like symptoms and post nasal drip. By the next month the patient
had severe pain between the eyes, daily dizziness along with other symptoms.
In November/December the post nasal drip improved. The patient had upper
stomach pain and was found to have a gall bladder polyp by ultrasound.
The patient had GERD, Gastro Esophageal Reflex Disease, along with other
symptoms. The patient had a number of emergency room visits for severe
GERD symptoms. Eventually a gastric-emptying study showed gastroparesis
of the antrum.

In May 2006 the patient had diffuse muscle fasciculations and numbness of his hands and feet, sharp jerking shooting
pain all over the body. In June 2006 the patient had a spinal tap that was completely normal. Lymeís disease antibody
was borderline positive although the patient had never been in the areas endemic for Lymeís disease. An Infectious
Disease physician felt the patient did not have active Lymeís disease. In the fall of 2006 the patient had a tilt test
that showed postural orthostatic tachycardia. The patient was given atenolol and felt much worse. The patient has not
worked since September 2006. Eventually the patient was treated with 6 months of intravenous Rocephin for Lymeís
disease without improvement of his symptoms. EBV and CMV IgG were positive. All the regular blood test results
including CBC, chemistry panel, TFT, CT scan, MRI scan, EMG continued to be normal. The patient was given Valcyte for
3 months without benefit. Subsequent MRI scan done showed a punctate white lesion on the surface of the left parietal
lobe which was not confirmed on a repeat MRI scan done six months later. Energy level was better for 3 out of 7 days
but he could only do 3 hours of light activity with frequent breaks. On the other 4 days the patient was practically
bedridden with energy level 0-1/10. He continues to have numbness, stabbing pain in the fingers and toes especially
when he sits down, along with neck stiffness.

Routine laboratory studies including TFT, ANA, RF, CRP, ESR, H. pylori antibody. Lymeís disease antibody done at Stoney
Brook Laboratory, celiac disease panel, urine heavy metal screening, SS-A, SS-B antibodies were negative. AST and ALT
were mildly elevated on two determinations. CSF, MS panel on June 3, 2006 was negative. CT of the sinus showed small
polyps within the maxillary sinuses. ENG and hearing test were normal. EGD and colonoscopy in January 2006 showed a
single sigmoid polyp. Stool studies were negative. The patient was treated with tapering course of prednisone in
November 2005. In June 2008, CVB 4 antibody titer was 1:640 (<1:10).

ASSESSMENT: Chronic fatigue syndrome with documented orthostatic hypotension, chronic dizziness
and other neurological symptoms, was most likely due to a chronic enterovirus infection since the initial symptoms
of infection were gastrointestinal. These viruses would enter through the GI tract by eating
contaminated food or drinking water, then disseminate to the brain, spinal cord, muscles and heart, most often
through the blood but sometimes in a retrograde manner through the nerve fibers, as has been documented with
enterovirus 71. The brain stem symptoms and orthostatic hypertension are all suggestive of viral infection in
those areas, but the lesions are probably too small to be seen by the usual imaging studies such as CT and MRI
scans. It is interesting that there is a lag time of several months between the initial GI symptoms and the
subsequent brain symptoms. This is actually typical of many of the patients who did not have flu-like symptoms
immediately before the onset of the CNS or muscles symptoms. The best explanation is that viruses disseminated to
the secondary sites, such as brain may not manifest until the initial immune response gradually subsides.

Although the diagnosis of Lymeís disease has been implicated in the endemic areas by a few investigators, this
patient was never in the endemic areas for Borrelia burgdorferi., and the final serology done in a reputable
laboratory showed totally negative results. Furthermore, the continuing GI symptoms or even respiratory symptoms
in other patients are inconsistent with Lymeís disease, since this infection is transmitted by a tick bite and
dissemination has been documented in the joints, heart and the brain. The lack of response to valcyte is not
surprising since the drug is used for herpes viruses and yet the patient has an enterovirus infection.

The treatment for orthostatic hypotension is not ideal. Many of the patients did not tolerate beta blocker.
Alternatively, midodrine starting at 2.5 mg t.i.d. then work up to 5 mg t.i.d. and increase further as tolerated,
may be helpful for some patients. Antiviral therapy is still the key to control enterovirus infection, which will
require development.

CASE 3.

15-year-old white male had recurrent upper respiratory tract infection since early childhood. The patient developed
asthma and was treated with steroids at least 3 or 4 times over the years. He was able to play soccer but would have
at least a brief relapse with symptoms of coughing, sore throat and fatigue for 7-10 days after playing in a tournament.

He was functional until September 2007 when he had bedridden fatigue, global headache, sore throat, insomnia, sinus
congestion and persistent cough after another episode of respiratory infections. The symptoms did not respond to
antibiotics or Elavil.

The results of EBV and CMV antibodies were consistent with prior infection. DNA test for CMV and EBV and Lymeís
disease antibody were negative. Thyroid function tests, CBC, chemistry panel were all normal or negative. The
patient was evaluated by other physicians who all concluded that the patient had a diagnosis of pediatric chronic
fatigue syndrome and subclass IgG deficiency. Immunologic workup by an immunologist showed a B-cell dysfunction in
that there is deficient memory for immunoglobulin production. Immunization with pneumococcus vaccine and HIB showed
a positive antibody response which declined at six months. He actually was started on IVIG but had a reaction to the
specific preparation of IVIG. The patient was treated with numerous antibiotics Biaxin, Augmentin, Cipro and Zithromax
but experienced questionable improvement. Sinus CT scan showed extensive inflammatory changes but no air-fluid level.
Previous cultures of sinus drainage have all been negative. Intravenous antibiotics did not help his symptoms.

The patient also had upper stomach pain, nausea, fullness after eating, diarrhea at least one time per week. He
underwent a colonoscopy and EGD with biopsy on February 14, 2007. Multiple biopsies of the esophagus, stomach,
duodenum, terminal ileum and various parts of the colon showed minimal inflammation but with prominent lymphoid
aggregates in practically every biopsy. The patient has not been able to attend school and could not participate
in competitive soccer and is basically homebound. He continues to have all the above symptoms of headache,
bedridden fatigue, mild myalgia.

ASSESSMENT & TREATMENT: Chronic fatigue syndrome in a pediatric patient with B-cell dysfunction, low
IgG1, IgG3 levels. The patient had frequent respiratory infections since childhood complicated by asthma. The patient
likely has a Th2-dominant response which could not eradicate viruses that become persistent in his body. Instead of
having numerous new infections, most of the episodes of the sinusitis were likely reactivation of the underlying viral
pathogen. This type of patient most likely has enteroviruses especially in view of the respiratory
and the GI involvement. The fatigue did not increase until later when he acquired another unique strain
of enterovirus. There was likely a significant shift of the T-cell response downward to allow reactivation of underlying
pathogens. The antibodies for Coxsackie B viruses and echoviruses (5/26 serotypes) were not significantly elevated. The
biopsies from his stomach and colon tested positive for enterovirus VP 1 protein, a more specific
indicator of persistent infection. Epigastric and right lower quadrant tenderness elicited by physical examinations
correlated well with finding of enterovirus protein in the stomach biopsies, and therefore is a valuable sign to
document in ME/CFS patients.

The patient was started back on another preparation of IVIG, which he tolerated well. He had improvement of the sinus
symptoms but remained quite fatigued.

CASE 4.

42-year-old white male who developed a viral illness in 1986 that lasted at least one year. The nature of the illness
was an upper respiratory infection associated with weakness, drowsiness, fatigue, sniffles, postnasal drip, dizziness
and some weight gain. He did have purulent sputum, which was treated with antibiotics, but the patient continued to
have significant respiratory congestion. Sinequan did help the insomnia and his energy level. He essentially recovered
in October 1987. The symptoms recurred in April 2003. The episode lasted at least two months, started off with sinus
infection then profound fatigue. He eventually recovered but still felt somewhat sluggish for several months. In
September 2003 the fatigue recurred with swollen left eyelid but did not have any significant eye disease by examination.
The fatigue actually improved after a cortisone shot followed by Medrol dosepak. The patient went back to work and yet
the symptoms recurred in late December associated with insomnia and GI upset but no diarrhea.

EGD and colonoscopy in January in 2004 showed no significant abnormalities. Biopsy of the stomach showed minimal
inflammatory changes. The patient could not get out of bed on most days. He had occasional night sweats associated
with increased fatigue, intense myalgia (muscle soreness), mild cognitive dysfunction, post-exertional malaise and
unrefreshing sleep.

Previous laboratory testing was essentially normal except for intermittent elevated liver enzyme to 65
(normal <40) in March 2003. Review of his blood work showed negative rheumatoid factor, anti-nuclear antibody,
erythrocyte sedimentation rate. Repeat testing in September 2003 showed EBV VCA IgG of 47, negative IgM; normal CBC.
Previous sinus CT on September 8, 2003 showed some paranasal sinus disease and a cyst in the right maxillary sinus.
ALT was elevated at 61 in January 2004 but other aspects of the chemistry panel, CBC, TSH were again normal.
Coxsackievirus B1-6 and Echovirus 6,79,11,30 antibody titers were negative.

PHYSICAL EXAMINATION: The patient looked mildly fatigued; not depressed. Vital signs normal.
The general examination was normal except for minimal throat erythema, minimally tender cervical lymph nodes and
moderate tenderness of the epigastrium, right lower and left lower abdomen. No muscle tenderness
or trigger points were demonstrated.

Stomach biopsy done in 2004 was positive for enterovirus protein when performed in 2007.

ASSESSMENT & TREATMENT: Chronic recurrent fatigue began as an initial episode in 1986 lasting one
year. The nature of the infection was not typical of EBV infection and the low EBV antibody was consistent with
this assessment. Acute EBV infection, or acute mononucleosis, does not present with nasal or sinus congestion,
rhinorrhea. This initial virus infection was probably enterovirus since other respiratory viruses, such as
adenoviruses, coronaviruses, influenza, parainfluenza, RSV or metapneumovirus typically would not cause symptoms
in immunocompetent patients for more than few weeks. The symptoms recurred few times over the next 20 years, mostly
brought on by another respiratory infection. The GI symptoms were largely dismissed as irritable bowel syndrome and
treated symptomatically. The stomach symptoms, such as nausea, indigestion, acid reflux, bloating with or without
meals are suggestive of chronic enterovirus infection, which was confirmed by enteroviral staining of his stomach
biopsy when the technique was developed. The patient was treated with a combination of alpha and gamma interferon
for one month and went into remission for about one and a half years.

CASE 5.

A 29-year-old white female developed recurrent sinus infection and severe vomiting during her second pregnancy 6
years earlier, though she did not have any difficulty with her first pregnancy. However, she had vomiting again
in her third pregnancy two years later and continued to have recurrent sinus congestion. In June 2004, the patient
developed sore throat and right cervical lymphadenopathy, lower abdominal pain, increasing nausea, sinus congestion.
The patient did not have any diarrhea. The patient was given amoxicillin with resolution of the sore throat in 5
days. The patient has been tired ever since. Initially her energy level was as low as 3/10 with pain over the neck,
shoulder, arm and increasing migraine headache. She did have mild night sweats, mild brain fog only with the headache.
The sinus congestion would worsen with her worst days. In general, energy level has improved in the last year and a
half. Now her energy level is about 5-6/10 but she still feels bad with a level of 3-4/10 at least twice a month. The
patient does not do exercise but is very busy taking care of three kids.

ASSESSMENT: Chronic fatigue syndrome that started with one enterovirus infection that dated back to
sinus/GI infection during her second pregnancy. This is likely enterovirus infection due to the nature of the symptoms.
However, the infection was not eradicated during pregnancy since the immune system was likely shifted to a Th2-dominant
response. The patient did have an endoscopy 1 1/2 years earlier, and a biopsy tested positive for enteroviral protein and
viral RNA. The patient responded to Chinese herbs.

CASE 6.

43-year-old white female developed right lower quadrant abdominal pain and constipation in June 2005, when she was
training for marathon. The pain was quite severe and lasted about a week. CT scan of the abdomen and pelvis was
negative. She rested at home and then went back to work. On July 4th the patient developed recurrent right lower
quadrant pain after she had a big feast. She had severe diarrhea. The patient had a colonoscopy, which was
essentially normal by biopsy. The patient was subsequently discharged although the diarrhea continued in September.
Capsule endoscopy was negative. The patient was given antibiotics without much response. EGD was not done. The
patient continued to have a severe sore throat. The patient had low-grade temperature from 100F to 101F along with
night sweats, fatigue, diffuse joint pain and myalgia of the right lower extremity.

In January 2006, the patient had significant sore throat, lymphadenopathy. The patient was given antibiotic with
subsequent increase in diarrhea. The patient developed increasing night sweats, fatigue, insomnia, irregular
menstrual period. Hormonal tests were normal in February 2006.

The patient also had right hip joint pain and had significant increase in blood pressure without documented renal
disease. The patient was placed on antihypertensive medication with improvement of the blood pressure.

The patient traveled all over Asia for many years. The patient did develop diarrhea around 2000 or 2001 which
lasted for a few months, which recurred a few times every few weeks. The patient had increased allergic rhinitis
and sinus congestion. In 2005, between January and June, the patient was training for a marathon before the
increase in symptoms. At the present time, the patient could not function for more than 1-2 hours /day before
having to lie down. She continued to have low-grade fever and some night sweats, difficulty with mental
concentration, fatigue, unrefreshing sleep, nausea and indigestion. Energy level was about 3-4/10 and 8/10 in
1/30 good day. The patient would crash the next day after a good day.

ASSESSMENT: Chronic fatigue syndrome
with prior gastrointestinal illness. The patient had prior episodes
of diarrhea back in 2000/2001 after she traveled to Asia, which raised
suspicion of enterovirus infection. In 2005, between January and June,
it was possible that the increase in physical exercise resulted in the
relapse of this chronic enterovirus infection. Within one month she
responded to Chinese herbs, and continued to take these herbs for more
than 1 1/2 years. Energy level is now 8/10 most of the time with only
few bad days (5/10) before her periods.

CASE 7.

A 17-year-old white male had frequent infections as a
child. The patient experienced sore throats at least 1-2 times a year,
and then developed asthma at age 7, which was treated with inhalers.
He started feeling tired along with experiencing thigh and leg pain
since about 4-5 years ago. The patient recalled he and his brother became
ill with vomiting, diarrhea, abdominal pain after eating at a local
Mexican restaurant. The parents did not get sick. The patient was hospitalized
for one day and sometime later developed fatigue, difficulty with concentration,
deep pressure-like headaches along with nausea and indigestion, but
no sore throat. His energy level has been about 3/10. The patient could
go to school from 8:00AM to 3:00PM, but after school falls asleep for
a long time and sometimes sleeps till the next morning. The brother
also developed intermittent epigastric pain and mild fatigue.

Laboratory studies included repeated complete blood counts and chemistry panels in February and March 2008, which
showed normal results. IgG level, IgA level, TSH, FSH, T4, testosterone levels were also normal. ANA, ESR, RF were
negative with a normal CH-50. A rheumatologist felt the patient did have fibromyalgia. The patient was treated with
Elavil and Neurontin with mild improvement. The patient did not respond to bio-feedback/hypnosis. He was found to be
allergic to cat and dog danders, olive trees, etc. Six months ago the patient developed symptoms of viral meningitis
which were treated symptomatically as an outpatient. After this episode, the patient developed marked increase in
fatigue, postexertional malaise, poor sleep with frequent awakening at night. He did have night sweats, mild arthralgia
along with the myalgia, but no rashes. His grades worsened with increasing cognitive dysfunction. The patient did see
Dr. St. Amand who felt the patient had fibromyalgia, but a 6-month course of guaifenesin did not help his symptoms.
The patient has tried Soma and Flexeril which made him more tired.

ASSESSMENT & TREATMENT: Chronic fatigue syndrome following repeated virus infection. At age 7 the
patient developed asthma following virus infection which is indicative of th2 response. 4 or 5 years ago the patient
developed vomiting and diarrhea after eating Mexican food which was followed by fatigue, myalgia, CNS dysfunction,
etc. The GI involvement and other symptoms of CFS are highly suggestive of chronic enterovirus infection, which
worsened after developing viral meningitis six months ago. The most common agent causing viral meningitis is
enterovirus. After repeated enterovirus infections, the patient seemed to do much worse. The patient had minimal
improvement of symptoms after IVIG, but now doing much better on oxymatrine, a Chinese herbal supplement.

CASE 8.

A 44 year-old female experienced a great deal of stress
in 2000 when she worked as a teacher and assistant principle. She became
more depressed and did not respond to anti-depressant. The patient was
already fatigued, but did not seek medical help during her busy summer
schedule. Myalgia and arthralgia started mainly in hands, wrists and
muscles around the joints, which were migratory in nature. She noticed
pain and spasms over her neck and both shoulders. The patient did not
have fever, but did have mild chills and mild night sweats. She had
unrefreshing sleep, cervical lymphadenopathy, sinus congestion, pharyngitis,
chest pain, headache, diarrhea and severe fatigue.

A medical evaluation revealed shoddy cervical lymph nodes
and diffuse muscle tenderness (trigger points). She was felt to have
depression and fibromyalgia. A complete blood count, comprehensive chemistry
panel, thyroid function test and erythrocyte sedimentation rate were
normal and a work-up for autoimmune diseases was negative. IgG antibody
to Epstein-Barr virus was positive with a negative IgM antibody. Treatment
with Paxil did not alleviate her symptoms. She had frequent dizziness,
unsteady gait and tingling of her hands. For the work-up of her abdominal
complaints, EDG did show mild gastritis, which responded to Prilosec.
A colonoscopic examination was negative.

Second rheumatology evaluation confirmed the diagnosis of fibromyalgia. The patient was treated with Ultram, Klonopin,
Celexa, Trazadone, which did help the pain, sleep and depression. However, the fatigue continued. The patient tried
Guaifenesin in the summer of 2002, but did not improve and experienced an increase of symptoms.

After she traveled to the east coast of the U.S., the
symptoms of fatigue, myalgia worsened for 6 weeks. The symptoms would
fluctuate every week, severe fatigue would last several days with energy
level of 1-2/10, then gradually improve to a level of 4/10 on her best
days. The patient had to quit working after one year of illness. The
patient had to have a wheelchair to get around the house after she got
back from her trip. All of the muscles and joints hurt after she performed
trivial activity. Now, the maximal exercise she can perform is walking
slowly for 15 minutes with post-exertional malaise whereas she could
jog for miles. Before she became ill she would rarely need to take a
nap, wheras now she must lie down very often. She slept poorly, awakening
q 3 hours. Even doing her hair will make her tired. She lost 10 pounds
since the onset of illness. The symptoms were much worse right before
her periods. She would have 5 good days in a month.

Past Medical History.Positive for IBS since 15 years of age. Shingles ≠ several episodes over the upper and mid-back,
treated with antivirals, last episode 8 years ago.

Assessment & Treatment:
Chronic fatigue syndrome and fibromyalgia ≠ the patientís symptoms started around 2000 perhaps after a subclinical
respiratory or GI infection. We have seen a number of patients who had prior histories of respiratory or GI infections
and deteriorated without a clear-cut, new episode of viral infection. The symptoms of a new infection may have been
interpreted as a flare of the prior infection. After complete evolution of the symptoms, enteroviral infection was
suspected and confirmed by the study of the stomach biopsies. The patient was under a great deal of emotional stress,
which could have shifted the immune response to the Th2 direction. The patient has fulfilled the 2 major and 4 minor
criteria for the diagnosis of CFS, as established by the CDC in 1994. Based on evidences found in animal model of
Coxsackie B virus infection and studies done by other investigators on patients with post-infectious fatigue syndrome,
there is little doubt that persistence of viral RNA in susceptible, long-living cells can elicit chronic inflammatory
reaction resulting in symptoms of CFS. The patient has not responded to interferon or a combination of Chinese herbs.
Her insurance would not pay for IVIG.